The persistent rise in the proportion of overweight individuals in Western society over the past 30 years has been associated with substantial excess morbidity and is widely recognized as a major public health concern. To address this problem, intensive efforts exist to clarify neuroendocrine contributions to weight gain. Starting with the isolation of leptin (1), a series of hormones acting centrally and peripherally to influence body mass have been discovered. Among these, the gastric peptide hormone acyl-ghrelin has generated considerable interest as an important stimulus for weight gain (2-5) and modulator of glucose homeostasis (6-8). Various strategies in therapeutic development have been described for the antagonism of acyl-ghrelin (9), although none has yet emerged as clinically beneficial.
The biosynthesis of acyl-ghrelin involves an unusual post-translational octanoylation of the serine at the 3 position of the ghrelin peptide. This octanoylation is necessary for its bioactivity, which occurs via interaction with the growth hormone secretagogue receptor (GHSR). The enzyme responsible for this esterification, ghrelin O-acyltransferase (GOAT), has recently been cloned (10, 11).
There remains a need in the art for improved therapeutic agents for use in the treatment of obesity and diabetes, especially ones that target neuroendrocrine pathways. In countering the global pandemic of obesity, which causes an estimated 10,000 premature deaths per week, an effective appetite-reduction medication can be potentially life-saving on a grand scale.